Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CMS) which can present as a remitting/relapsing, primary progressive, secondary progressive or progressive relapsing form. Experimental autoimmune encephalomyelitis (EAE), a frequently studied animal model for MS, is inducible in the commonly used C57BL/6 mouse, which develops a progressive course of EAE when immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. A major focus of research in EAE and MS has been what causes progression of disease and is there a signal which can be used to predict a relapse or worsening of disease. Migration inhibitory factor (MIF) has recently been re-discovered as an inducer of pro- inflammatory cytokines and an antagonist of glucocorticoid hormones. We examined the role of MIF in acute and chronic EAE using MIF knock-out mice. We found that MIF-/- mice showed signs of acute EAE identical to wild type (WT) controls but did not exhibit progression of disease. MIF-/- mice showed elevated levels of corticosterone and decreased levels of pro-inflammatory cytokines. In light of these findings and reports by others that colitis is suppressed in MIF-deficient animals, we pose the hypothesis that MIF derived from myeloid cells is necessary for progression of EAE. We will first determine the cellular source of MIF which is necessary for progressive EAE using a series of bone marrow chimeras in which various cell types are rendered MIF deficient. Second, we will gain a better understanding of the role played by MIF in disease progression by examining priming, CNS histopathologic changes, glucocorticoid hormone release, and cytokine changes. At the completion of these studies, we will have determined the source of the biologically relevant MIF and will have a clearer picture of the role played by MIF in causing progression of EAE. During the course of this project, we will repeatedly evaluate the possibility that MIF could serve as a target for new therapies in MS.
TO PUBLIC HEALTH: Multiple sclerosis is a disease affecting over 300,000 persons in the US which affects their ability to work and lead a productive life. It begins early in life and often progresses slowly leading to severe disability. This project studies a key factor involved in disease progression and will identify specific points in disease when therapeutic intervention is likely to be successful.
|Williams, Jessica L; Gatson, NaTosha N; Smith, Kristen M et al. (2013) Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity. Clin Immunol 149:236-43|
|Cox, Gina Mavrikis; Kithcart, Aaron P; Pitt, David et al. (2013) Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. J Immunol 191:1043-54|
|Alexander, Jessica K; Cox, Gina M; Tian, Jin-Bin et al. (2012) Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress. Exp Neurol 236:351-62|
|Smith, Kristen M; Guerau-de-Arellano, Mireia; Costinean, Stefan et al. (2012) miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol 189:1567-76|
|Williams, Jessica L; Kithcart, Aaron P; Smith, Kristen M et al. (2011) Memory cells specific for myelin oligodendrocyte glycoprotein (MOG) govern the transfer of experimental autoimmune encephalomyelitis. J Neuroimmunol 234:84-92|
|Kithcart, Aaron P; Cox, Gina M; Sielecki, Thais et al. (2010) A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease. FASEB J 24:4459-66|
|Song, Fei; Wardrop, Richard M; Gienapp, Ingrid E et al. (2008) The Peyer's patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomylelitis (EAE). J Autoimmun 30:230-7|
|Barbi, Joseph; Cummings, Hannah E; Lu, Bao et al. (2008) PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells. Blood 112:3048-51|